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Myasthenia Gravis - Pathophysiology, Cl. Features, DD

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Myasthenia Gravis - Pathophysiology, Cl. Features, DD

  1. 1. PATHOPHYSIOLOGY CLINICAL FEATURES AND DIFFERENTIAL DIAGNOSES Myasthenia gravis Dr JISHANTH M Prof Dr A Gowrishankar’s Unit Dept. of Internal Medicine
  2. 2. INTRODUCTION <ul><li>The most significant development: </li></ul><ul><li>The demonstration of An Immunologic Mechanism operative at the neuromuscular junction </li></ul><ul><li>Result is a failure of effective neuromuscular transmission on the postsynaptic side </li></ul>
  3. 3. THE NEUROMUSCULAR JUNCTION
  4. 4. PATHOPHYSIOLOGY <ul><li>Antibodies to AChR protein : </li></ul><ul><li>85 % of patients with generalized myasthenia and 60% of those with ocular myasthenia shows AChR Antibodies </li></ul><ul><li>Anti-MuSK Ab (40% of seronegative cases) </li></ul><ul><li>An immune response to muscle-specific kinase (MuSK) can also result in myasthenia gravis, possibly by interfering with “ AChR clustering” </li></ul><ul><li>How do these antibodies act? </li></ul><ul><li>Blocks the binding of ACh to the AChR. </li></ul><ul><li>INCREASES THE DEGRADATION rate of AChR ANTIBODIES-> CROSS LINKING OF RECEPTORS -> ->CLUSTERING -> ENDOCYTOEIS -> DEGRADATION </li></ul><ul><li>A complement-mediated destruction of the postsynaptic folds. </li></ul><ul><li>The latter two mechanisms would be expected to reduce the number of AChR at the synapse. </li></ul>
  5. 6. Myasthenia Gravis <ul><ul><ul><li>AChRs </li></ul></ul></ul>Antibodies Simplified Motor Endplates
  6. 7. PATHOLOGY <ul><li>The muscle fibers are generally intact </li></ul><ul><li>In fatal cases with extensive paralysis, </li></ul><ul><li>“ Segmental necrosis with variable regeneration” </li></ul><ul><li>Scattered aggregates of lymphocytes, “Lymphorrhages” especially associated with thymomas </li></ul><ul><li>MOTOR END PLATE: </li></ul><ul><li>a reduction in the area of the nerve terminal, </li></ul><ul><li>a simplification of the postsynaptic region (sparse, shallow, abnormally wide or absent secondary synaptic clefts) </li></ul><ul><li>a widening of the primary synaptic cleft </li></ul><ul><li>PRESYNAPTIC VESICLES AND NERVE TERMINALS ARE NORMAL </li></ul>
  7. 8. THYMIC AND OTHER ASSOCIATED DISORDERS <ul><li>Thymus is abnormal in ~75% of patients with MG </li></ul><ul><li>In ~65% the thymus is &quot; hyperplastic ,&quot; </li></ul><ul><ul><li>(a nonneoplastic lymphofollicular hyperplasia of the thymic medulla) with the presence of active germinal centers detected histologically </li></ul></ul><ul><li>10% of patients have thymic tumors (“ neoplastic” ) </li></ul><ul><li>Thymomas with malignant characteristics may spread locally </li></ul><ul><li>Upon distant spread, the lungs and liver are usually affected. </li></ul><ul><li>Muscle-like cells within the thymus (myoid cells) which bear AChRs on their surface may trigger immune response </li></ul>
  8. 9. Pathologic Features of the Thymus <ul><li>Hyperplasia of the medulla characterized by lymphoid follicles with active germinal centers. The cells in the centers of the follicles are histiocytes; </li></ul><ul><li>Immunoglobulin G (IgG) is elaborated in the germinal follicles. </li></ul><ul><li>These resemble the cellular reaction that is observed in the thyroid of Hashimoto thyroiditis . </li></ul><ul><li>THYMOMAS </li></ul><ul><li>Two forms have been described: </li></ul><ul><li>Composed of histiocytic cells like the reticulum cells in the center of the follicles </li></ul><ul><li>Predominantly lymphocytic and considered to be lymphosarcomatous </li></ul>
  9. 10. <ul><li>The immune effector cells in myasthenia gravis are both T and B cells. </li></ul><ul><li>Sensitized T cells and complement play a role in continued stimulation of B cells and in cell mediated post synaptic destruction </li></ul>
  10. 11. CLINICAL FEATURES <ul><li>Prevalence: 1-7 in 10,000 </li></ul><ul><li>Affect all age groups </li></ul><ul><li>Usual age at onset: BIMODAL PEAK </li></ul><ul><li>20-30 yrs(young women), 50-60 yrs(older men) </li></ul><ul><li>< 10% occur in children <10 yrs </li></ul><ul><li>When <40 yrs f:m = 2-3:1, males more affected in elderly(3:2) </li></ul><ul><li>Overall F:M = 3:2 </li></ul><ul><li>Familial occurrence is known, but rare </li></ul><ul><li>More common is a family history of one or the other autoimmune diseases , and suggests partial genetic predisposition </li></ul><ul><li>Reports of the concurrence of myasthenia and MULTIPLE SCLEROSIS </li></ul>
  11. 12. CLINICAL PRESENTATION <ul><li>Repeated or persistent activity of a muscle group exhausts its contractile power( fatigability ), leading to a progressive paresis, and rest partially restores strength </li></ul><ul><li>There is special vulnerability of certain muscles </li></ul><ul><ul><li>( the eyelids and the muscles of the eyes, face, jaws, throat, and neck, are the first to be affected ) </li></ul></ul><ul><li>Limb muscle weakness as the initial complaint is less frequent. </li></ul>
  12. 13. CLINICAL PRESENTATION <ul><li>Fluctuating weakness increased by exertion </li></ul><ul><ul><li>Weakness increases during the day and improves with rest </li></ul></ul><ul><li>Levator palpebrae &Extraocular muscle weakness </li></ul><ul><ul><li>Ptosis/diplopia is presenting symptom in 50% of patients and ↑ during the course of disease in 90% </li></ul></ul><ul><ul><li>If associated with weakness of closure—almost diagnostic if “PUPILS ARE SPARED” </li></ul></ul><ul><li>Head extension and flexion weakness </li></ul><ul><ul><li>More sensitive in demonstrating generalised disease </li></ul></ul>
  13. 14. OSSERMAN Classification <ul><li>Class I Any ocular muscle weakness </li></ul><ul><li>ClassII Mild weakness other than ocular </li></ul><ul><ul><li>IIa Predominantly limb,axial, or both </li></ul></ul><ul><ul><li>IIb Predominantly orpharyngeal/respiratory </li></ul></ul><ul><li>Class III Moderate weakness other than ocular </li></ul><ul><ul><li>IIIa Predominantly limb,axial, or both </li></ul></ul><ul><ul><li>IIIb Predominantly orpharyngeal/respiratory </li></ul></ul><ul><li>Class IV Severe weakness other than ocular </li></ul><ul><ul><li>IVa Predominantly limb,axial, or both </li></ul></ul><ul><ul><li>IVb Predominantly orpharyngeal/respiratory </li></ul></ul><ul><li>Class V Intubation with/without ventilation </li></ul>
  14. 15. PROGRESSION OF DISEASE <ul><li> Mild to severe…..over weeks to months </li></ul><ul><ul><li>Spreads from ocular to facial to bulbar to truncal and limb muscles </li></ul></ul><ul><ul><li>Symptoms may remain limited to EOM and eyelid muscles for yrs </li></ul></ul><ul><ul><li>The disease remains ocular in 16% of patients </li></ul></ul>
  15. 16. REMISSIONS <ul><ul><li>Spontaneous remissions rare, most remissions with treatment occur within the first three years </li></ul></ul><ul><ul><li>If remission lasts >1 yr and recurs disease tend to be progressive. </li></ul></ul><ul><ul><li>Isolated ocular myasthenia > 1 yr, subsequent generalisation is only 16% </li></ul></ul><ul><ul><li>The course is altered by thymectomy (even drug free remissions) </li></ul></ul>
  16. 17. BASIC PHYSICAL EXAMINATION <ul><ul><li>Sensory examination and DTR’s are normal </li></ul></ul><ul><ul><li>Muscle strength testing </li></ul></ul><ul><ul><li>Recognize patients who may develop respiratory failure (i.e. difficult breathing) </li></ul></ul>
  17. 18. CLINICAL PRESENTATION <ul><li>MUSCLE STRENGTH </li></ul><ul><ul><li>Ocular muscle weakness </li></ul></ul><ul><ul><li>Facial muscle weakness </li></ul></ul><ul><ul><li>Bulbar muscle weakness </li></ul></ul><ul><ul><li>Limb muscle weakness </li></ul></ul><ul><ul><li>Respiratory weakness </li></ul></ul>Bulbar Muscles
  18. 19. 1. OCULAR MUSCLE WEAKNESS <ul><ul><li>ASYMMETRIC </li></ul></ul><ul><ul><li>Usually affects more than one extraocular muscle and is not limited to muscles innervated by one cranial nerve </li></ul></ul><ul><ul><li>Weakness of lateral and medial recti may produce a pseudo internuclear opthalmoplegia </li></ul></ul><ul><ul><li>Ptosis is caused by Levator palpebrae weakness </li></ul></ul><ul><ul><li>“ Sustained upward gaze for 30 seconds” </li></ul></ul><ul><ul><li>Diplopia is very common </li></ul></ul><ul><ul><li>“ Lid-twitch” sign , Repeated ocular versions </li></ul></ul><ul><ul><li>Bright sunlight aggravate the ocular signs and COLD improves them </li></ul></ul>
  19. 20. 2. FACIAL MUSCLE WEAKNESS <ul><li>Facial muscle weakness is almost always present </li></ul><ul><ul><li>bilateral facial muscle weakness </li></ul></ul><ul><ul><li>Sclera below limbus may be exposed due to weak lower lids </li></ul></ul><ul><ul><li>Muscles of facial expression </li></ul></ul>
  20. 21. 3. BULBAR MUSCLE WEAKNESS <ul><li>Bulbar muscle weakness ( more in Anti MuSK Ab positive cases) </li></ul><ul><ul><li>Palatal muscles </li></ul></ul><ul><ul><ul><li>“ Nasal voice”, nasal regurgitation </li></ul></ul></ul><ul><ul><ul><li>Chewing may become difficult </li></ul></ul></ul><ul><ul><ul><li>Severe jaw weakness may cause jaw to hang open </li></ul></ul></ul><ul><ul><ul><li>Swallowing may be difficult and aspiration may occur with fluids—coughing and choking while drinking </li></ul></ul></ul><ul><ul><li>Neck muscles </li></ul></ul><ul><ul><ul><li>Neck flexors affected more than extensors </li></ul></ul></ul>
  21. 22. 4. LIMB MUSCLE WEAKNESS <ul><ul><li>Upper limbs more common than lower limbs </li></ul></ul><ul><ul><li>Proximal > than distal muscles </li></ul></ul><ul><ul><li>Usually asymmetric weakness </li></ul></ul>Upper Extremities Deltoids Wrist extensors Finger extensors Triceps > Biceps Lower Extremities Hip flexors (most common) Quadriceps Hamstrings Foot dorsiflexors Plantar flexors
  22. 23. 5. RESPIRATORY MUSCLE WEAKNESS <ul><ul><li>Weakness of the intercostal muscles and the diaphragm may result in CO2 retention due to hypoventilation </li></ul></ul><ul><ul><ul><li>May cause a neuromuscular emergency </li></ul></ul></ul><ul><ul><li>Weakness of pharyngeal muscles may collapse the upper airway </li></ul></ul><ul><ul><li>Monitor negative inspiratory force, vital capacity and tidal volume </li></ul></ul><ul><ul><li>Do NOT rely on pulse oximetry </li></ul></ul><ul><ul><ul><li>Arterial blood oxygenation may be normal while CO2 is retained </li></ul></ul></ul>
  23. 24. <ul><li>As the disease progresses it can involve the external sphincters of bowel and bladder. </li></ul><ul><li>A temporary increase in weakness may follow vaccination, menstruation and exposure to extremes of temperature </li></ul><ul><li>Weakened muscles “ NEVER GO FOR ATROPHY” </li></ul><ul><li>Tendon reflexes are retained till late </li></ul><ul><li>Smooth and cardiac muscles are not involved </li></ul><ul><li>Tongue may display a central and 2 lateral longitudinal furrows “trident tongue” </li></ul><ul><li>Symptoms may appear first during pregnancy, puerperium or in response to drugs used during anesthesia. </li></ul><ul><li>Transient NEONATAL MYASTHENIA </li></ul>
  24. 25. CO-EXISTING AUTOIMMUNE DISEASES <ul><ul><li>Hashimoto’s thyroiditis/thyrotoxicosis </li></ul></ul><ul><ul><ul><li>Occurs in 5-10%% MG patients </li></ul></ul></ul><ul><ul><ul><li>Weakness may not improve with treatment of MG alone in patients with co-existing hyperthyroidism </li></ul></ul></ul><ul><ul><li>Rheumatoid arthritis </li></ul></ul><ul><ul><li>Scleroderma </li></ul></ul><ul><ul><li>Lupus erythematosus, </li></ul></ul><ul><ul><li>Sj ӧ gren syndrome, </li></ul></ul><ul><ul><li>mixed connective tissue disease </li></ul></ul><ul><ul><li>anticardiolipin antibody </li></ul></ul><ul><ul><li>polymyositis </li></ul></ul>
  25. 26. MYASTHENIC CRISIS <ul><li>A rapid and severe deterioration of myasthenia called “myasthenic crisis” can bring patient to the brink of respiratory failure and quadriparesis in hours </li></ul><ul><li>A respiratory infection or a sedative medication with NM block may be the reason </li></ul><ul><li>It can develop at any time after the diagnosis of myasthenia </li></ul><ul><li>Anticipate if patient is restless, anxious with diaphoresis and develops tremor. </li></ul><ul><li>Require respiratory support </li></ul>
  26. 27. NEUROLOGIC CONDITIONS MIMICKING MYASTHENIA GRAVIS <ul><li>CONDITION SIGNS AND SYMPTOMS </li></ul><ul><li>ALS Asymmetric muscle weakness and atrophy </li></ul><ul><li>Botulism Generalized limb weakness </li></ul><ul><li>Guillain-Barré syndrome Ascending limb weakness </li></ul><ul><li>Inflamm. muscle disorders Proximal symmetric limb weakness </li></ul><ul><li>Lambert-Eaton syndrome Proximal symmetric limb weakness </li></ul><ul><li>Multiple sclerosis Bilateral internuclear ophthalmoplegia </li></ul><ul><li>Periodic paralysis Intermittent generalized muscle weakness </li></ul><ul><li>Thyroid disease </li></ul><ul><li>Congenital myasthenic syndromes </li></ul><ul><li>Brainstem syndromes/encephalitis </li></ul>
  27. 28. LAMBERT-EATON SYNDROME <ul><li>Presynaptic disorder of NMJ </li></ul><ul><li>Antibodies against P/Q type calcium channels at the motor nerve terminals ( +ve in 85% ) </li></ul><ul><li>Impaired release of Ach from nerve terminals </li></ul><ul><li>Muscle weakness similar t MG ( proximal>distal, CN involvement >70%) </li></ul><ul><li>“ Warming up ” phenomenon </li></ul><ul><ul><ul><li>Depressed/absent reflexes </li></ul></ul></ul><ul><ul><ul><li>Autonomic changes </li></ul></ul></ul><ul><ul><ul><li>Incremental response to RNS </li></ul></ul></ul><ul><li>Associated with Ca Lung(small cell Ca).. “paraneoplastic” </li></ul><ul><li>Treatment: Immunosuppression; plasmapheresis; 3,4-DAP; pyridostigmine </li></ul>
  28. 29. DRUGS PRECIPITATING MYASTHENIA <ul><li>Anti-infective Agents Cardiovascular Agents Other Agents </li></ul><ul><li>Aminoglycosides Propranolol Chloroquine </li></ul><ul><li>Ampicillin Verapamil Corticosteroids </li></ul><ul><li>Ciprofloxacin Quinidine “d-penicillamine” </li></ul><ul><li>Erythromycin Procainamide Phenytoin   </li></ul><ul><li>Imipenem Propafenone Mydriatics </li></ul><ul><li>Kanamycin Acebutolol Trihexyphenidyl </li></ul><ul><li>Pyrantel Practolol Interferon </li></ul><ul><li>Timolol Trimethadione </li></ul><ul><li>Oxyprenolol </li></ul>
  29. 34. Prognosis <ul><li>Long-term outlook better for children than adults </li></ul><ul><li>Life expectancy slightly reduced </li></ul><ul><li>Most favorable outcome for bulbar weakness </li></ul><ul><li>Drug free remissions possible with thymectomy </li></ul><ul><li>Death rate reduced from 30% to <5% with pharmacotherapy and surgery </li></ul>
  30. 35. Differential diagnoses <ul><li>Lambert-Eaton Myasthenic Syndrome </li></ul><ul><li>Oaculopharyngeal muscular dystrophy </li></ul><ul><li>Multiple Sclerosis </li></ul><ul><li>Botulism </li></ul><ul><li>Brainstem syndromes </li></ul><ul><li>Brainstem gliomas </li></ul><ul><li>Thyroid disease </li></ul><ul><li>Sarcoidosis and Neuropathy </li></ul><ul><li>Amyotropic Lateral Sclerosis </li></ul><ul><li>Basilar Artery Thrombosis </li></ul><ul><li>Cavernous sinus syndromes </li></ul><ul><li>Dermatomyositis </li></ul><ul><li>Congenital myasthenic syndromes </li></ul><ul><li>Drugs/Antibiotics </li></ul>

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